Estrogen controls PKCe-dependent mechanical hyperalgesia through direct action on nociceptive neurons

Protein kinase C epsilon (PKCe) is an important intracellular signaling molecule in primary afferent nociceptors, implicated in acute and chronic inflammatory as well as neuropathic pain. In behavioral experiments inflammatory mediators produce PKCe-dependent hyperalgesia only in male rats. The mechanism underlying this sexual dimorphism is unknown. We show that the hormone environment of female rats changes the nociceptive signaling in the peripheral sensory neuron. This change is maintained in culture also in the absence of a gender-simulating environment. Stimulation of b2-adrenergic receptors (b2-AR) leads to PKCe activation in cultured dorsal root ganglia (DRG) neurons derived from male but not from female rats. Addition of estrogen to male DRG neurons produces a switch to the female phenotype, namely abrogation of b2-AR-initiated activation of PKCe. Estrogen interferes downstream of the b2-AR with the signaling pathway leading from exchange protein activated by cAMP (Epac) to PKCe. The interfering action is fast indicating a transcriptional-independent mechanism. Estrogen has a dual effect on PKCe. If applied before b2-AR or Epac stimulation, estrogen abrogates the activation of PKCe. In contrast, estrogen applied alone leads to a brief translocation of PKCe. Also in vivo the activity of estrogen depends on the stimulation context. In male rats, intradermal injection of an Epac activator or estrogen alone induces mechanical hyperalgesia through a PKCe-dependent mechanism. In contrast, injection of estrogen preceding the activation of Epac completely abrogates the Epac-induced mechanical hyperalgesia. Our results suggest that gender differences in nociception do not reflect the use of generally different mechanisms. Instead, a common set of signaling pathways can be modulated by hormones.